2. Clinics and Pathology

t(6;9)(p22;q34) is a rare subtype of pediatric AML earlier only described in small series and case reports (Gupta, et al 2010, Ishiyama, et al 2012, Slovak, et al 2006). Two large studies both published in 2014 described the clinical, morphologic, and genetic characteristics: the I-BFM-study including 62 children of which 54 was diagnosed as AML and 8 as MDS, and the COG study investigating 48 children all diagnosed as AML (Sandahl, et al 2014, Tarlock, et al 2014). This review is based upon the 110 children from these two series. There are no pediatric studies of stem cell origin. AML in children with t(6;9) is associated with French-American-British (FAB) type M2 (44%) and FAB type M4 (25%) (Sandahl, et al 2014, Tarlock, et al 2014).

Epidemiology

The t(6;9)(p22;q34) was first described in a pediatric patient in 1982 (Kaneko, et al 1982). It is rare, found in only about 1% of all pediatric AML (Sandahl, et al 2014, Slovak, et al 2006, Tarlock, et al 2014) and associated with late onset with a median age 11 years and no patients below 2 years of age (Sandahl, et al 2014, Tarlock, et al 2014). There is an equal sex distribution with 53% males.

Cytology

Basophilia is common in adults with t(6;9). In the I-BFM study, peripheral blood smears from 11 children and bone marrow smears from 15 children with t(6;9)(p22;q34) were evaluable for central review (Sandahl, et al 2014). All had mild to moderate bilinear dysplasia. Basophils were present in five patients (33%), four of which had 2% basophils, one patient (6%) had 1% basophils, none had > 2%. From the remaining 47 AML patients, reports on basophils were available in 16 cases; four patients had 1-2% basophils in BM smears, one had 0.4%, and no basophils were reported in the remaining 11. No Auer rods were seen in this reviewed pediatric series. Pseudo-Pelger cells were found in all reviewed material. Furthermore, almost all had tadpole blasts and many have bilobar blasts, both characteristic of AML-M3. However no patients were classified as FAB M3.

It has been suggested that Hematopoietic stem cell transplantation (HSCT) in first complete remission may improve outcome. In the I-BFM-study, the 5-year event-free survival was improved among patients treated the HSCT in CR1 compared with chemotherapy alone (68% vs. 18%; P

3. Genetics

The t(6;9) is often associated with FLT3-ITD reported in 42% to 69% (Sandahl, et al 2014, Slovak, et al 2006, Tarlock, et al 2014). In the I-BFM study, the gene expression profile was analyzed in 297 pediatric AML patients including eight t(6;9) AML cases. The t(6,9) cases had a significant signature with high expression levels of HOXA and the HOXB (HOXB2, (HOXB3, (HOXB4, HOXB5, HOXB6, HOXB8, and HOXB9) genes described previously (Hollink, et al 2011) but also with high expression of HIST2H4A, PRDM2 (RIZ), SESN1, and EYA3 (Sandahl, et al 2014).

4. Cytogenetics

Cytogenetics Morphological

The translocation is easily detected by conventional karyotyping, only 4/62 pediatric cases were discovered solely by FISH or PCR (Sandahl, et al 2014).

Additional anomalies

t(6;9)(p22;q34) often presents as the sole cytogenetic abnormality (81%). (Gupta, et al 2010). Additional abnormalities are described in 12-19%. (Sandahl, et al 2014) Recurrent aberrations in addition to t(6;9) have been described in 19% with loss of chromosome Y in three boys and trisomy 8 and trisomy 13 each present in three cases, either alone or combined (Sandahl, et al 2014).

6. Result of the chromosomal anomaly

Hybrid gene

Description

5' DEK - 3' NUP214 on der(6); head to tail DEK/NUP214 fusion gene (SET/NUP214 exceptional); breakpoint clusters in a single intron of 8 kb (ICB9: 'intron containing breakpoint 9') in NUP214, and in a single intron (of 12 kb) as well (ICB6) in DEK.

Transcript

5.5 kb RNA; no NUP214-DEK reciprocal transcript on chromosome 9.

Detection

RNA-PCR.

Fusion Protein

Description

165 kDa; N-term with almost the entire DEK protein fused to the C-terminal two-thirds of the NUP214 protein.

Expression Localisation

Nuclear localisation.

7. Bibliography

The t(6;9)(p22;q34) in myeloid neoplasms: a retrospective study of 16 cases